1. Field of the Invention
The present invention relates to stable solutions of mitomycin C which may be injected directly or diluted with sterile water or other suitable diluent for parenteral administration.
2. Description of the Prior Art
Mitomycin C is an antineoplastic antibiotic which is isolated from the fermentation of Streptomyces caespitosus. It is administered parenterally for the treatment, inter alia, of gastric carcinoma, pancreatic carcinoma, breast carcinoma, head and neck carcinoma, biliary carcinoma, lung carcinoma, bladder carcinoma and cervical carcinoma.
Mitomycin C is currently being marketed by Bristol-Myers Company under the tradename Mutamycin.RTM. as a lyophilized dosage form containing mannitol. Vials containing 20 and 40 mg mitomycin C are reconstituted with Sterile Water for Injection at 0.5 mg/ml and the reconstituted solutions are reported to be stable for 7 days at room temperature or 14 days under refrigeration.
It would be desirable to have a solution form of mitomycin C which would not require reconstitution prior to use. Improper reconstitution of a lyophilized product sometimes results in the formation of air-borne droplets ("blow-back") which, in the case of a potent antitumor agent such as mitomycin C, may be a health hazard to the personnel making up the solution for injection. Also, production of the present lyophilized mitomycin C product is quite costly, and a solution dosage form would be expected to have a lower cost of goods.
The stability and mechanisms of degradation of mitomycin C and its analogs in aqueous solutions have been the subject of many investigations.sup.1-11. Degradation in aqueous solutions is affected by acidic or alkaline pH, buffers and temperature. At pH below 7, mitomycin C is converted to 1-hydroxy-2,7-diaminomitosanes, and at pH above 7 it is hydrolyzed to 7-hydroxymitosane. Maximum stability is observed at about pH 7-8. In water at 25.degree. C., mitomycin C loses 10% potency in about 40 days. Diluted in i.v. fluids at room temperature to a concentration of 20-40 mcg/mL, it is stable for the following times: 5% dextrose injection, 3 hours; 0.9% sodium chloride injection, 12 hours; sodium/lactate injection, 24 hours.sup.12.
These data suggest that formulation of a ready-to-use aqueous solution of mitomycin C would be impossible, even when stored under refrigeration. The present inventors have found no report of the stability of mitomycin C in non-aqueous solvents suitable for parenteral administration. Since the prior art teaches that water rapidly induces mitomycin C degradation, however, one would expect that optimum stability would only be possible in solvents with very low water content.
U.S. Pat. No. 4,684,630 describes a method of parenterally delivering aqueous-unstable drugs which includes the aqueous dilution of a stable, anhydrous organic solution having the drug dissolved therein. Methods for preparation of stable solutions of the anticancer drugs, 5-azacytosine arabinoside and 5-azacytidine, are disclosed in which anhydrous solutions in dimethylsulfoxide or dimethylacetamide are diluted with an aqueous solution immediately prior to intravenous injection. There is no disclosure, however, of mitomycin C solutions.
It is an object of the present invention to provide a mitomycin C solution dosage form which is stable (.ltoreq.10% potency loss) for at least two years under refrigeration (4.degree. C.) and which can be injected directly or diluted with water or other aqueous vehicle for parenteral administration.